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Regulation of Cell Polarity by Exocyst-Mediated Trafficking

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Regulation of Cell Polarity by Exocyst-Mediated Trafficking Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Regulation of Cell Polarity by Exocyst-Mediated Trafficking Noemi Polgar and Ben Fogelgren Department of Anatomy, Biochemistry and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii 96813 Correspondence: [email protected] One requirement for establishing polarity within a cell is the asymmetric trafficking of intra- cellular vesicles to the plasma membrane. This tightly regulated process creates spatial and temporal differences in both plasma membrane composition and the membrane-associated proteome. Asymmetric membrane trafficking is also a critical mechanism to regulate cell differentiation, signaling, and physiology. Many eukaryotic cell types use the eight-protein exocyst complex to orchestrate polarized vesicle trafficking to certain membrane locales. Members of the exocyst were originally discovered in yeast while screening for proteins required for the delivery of secretory vesicles to the budding daughter cell. The same eight exocyst genes are conserved in mammals, in which the specifics of exocyst-mediated traf- ficking are highly cell-type-dependent. Some exocyst members bind to certain Rab GTPases on intracellular vesicles, whereas others localize to the plasma membrane at the site of exocytosis. Assembly of the exocyst holocomplex is responsible for tethering these vesicles to the plasma membrane before their soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated exocytosis. In this review, we will focus on the role and regulation of the exocyst complex in targeted vesicular trafficking as related to the establish- ment and maintenance of cellular polarity. We will contrast exocyst function in apicobasal epithelial polarity versus front–back mesenchymal polarity, and the dynamic regulation of exocyst-mediated trafficking during cell phenotype transitions. symmetric membrane trafficking is a critical man 1979; Novick et al. 1980). Differential sed- Amechanism by which cell polarity is estab- imentation in a density gradient enabled the lished and maintained. It is becoming evident identification of abnormally heavy yeast cells that a large variety of eukaryotic cells can use the harboring mutations in genes critical for the octameric exocyst protein complex as a “Swiss budding of the daughter cell. Later, eight of army knife” to execute a diverse number of po- the identified genes, Sec3, Sec5, Sec6, Sec8, larized trafficking processes. Members of the Sec10, Sec15, Exo70, and Exo84 (also called exocyst complex were first identified as regula- EXOC1–8, respectively) were shown to encode tors of polarized exocytosis in the budding yeast proteins that copurified with each other, and Saccharomyces cerevisiae, during a genetic this interacting complex was named the exocyst screen of secretory mutants (Novick and Schek- (Terbush et al. 1996; Guo et al. 1999a). This 750- Editor: Keith E. Mostov Additional Perspectives on Cell Polarity available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a031401 1 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press N. Polgar and B. Fogelgren kDa holocomplex is highly conserved through- bly (Fig. 1). The exocyst belongs to the family of out the eukaryotic kingdoms and null mutants complexes associated with tethering containing of individual subunits have shown early lethal- helical rods (CATCHR), in which the subunits ity in multicellular organisms (Friedrich et al. show generally low sequence homology, but 1997; Murthy et al. 2003; Fogelgren et al. 2015; have conserved helical bundles packed together Mizuno et al. 2015). into long rod-like structures (Chia and Gleeson Studies of the molecular mechanisms of 2014). Quick-freeze/deep-etch electron mi- exocyst function have been aided by emerging croscopy studies suggested that the exocyst knowledge of the exocyst’s structure and assem- subunits assemble in a side-by-side fashion, A Primary cilium B ERK1/2 Tight junction Rab11 P Crumbs complex GTP Sec15 Rabin8 PAR complex Vesicle Rab8 GTP Sec10 Adherens junction Vesicle Rab8-GDP Scribble complex C Sec15 Sec8 Exocyst Vesicle Exo84 Sec6 Sec5 Desmosome Sec10 Par GTPases complex PIPK1γ Cytoplasm Exo70 Sec3 Site of exocytosis Figure 1. Exocyst function in epithelial polarity. (A) The Rab11–Rabin8–Rab8 cascade facilitates Sec15 binding to the secretory vesicle. (B)PIPKg activity leads to a localized accumulation of the membrane phospholipid phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P2) (marked turquoise). By binding these phospholipids, Exo70 and Sec3 act as spatial landmarks for exocytosis at the plasma membrane. (C) The exocyst complex regulates polarity establishment and maintenance in association with GTPases, membrane phospholipids, and polarity complexes, and by trafficking secretory vesicles to several different membrane domains of epithelial cells. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a031401 Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Cell Polarity and Exocyst-Mediated Trafficking forming a T- or Y-shaped complex, in which the branes at the site of exocytosis independently of amino-terminal arms are responsible for mem- actin polymerization, and Exo70 could arrive to brane tethering and regulatory interactions and polarized sites via both actin-dependent and the carboxy-terminal domains pack together in -independent routes (Finger et al. 1998; Boyd parallel (Hsu et al. 1998; Matern et al. 2001; et al. 2004; Zajac et al. 2005; Liu and Novick Munson and Novick 2006). Early work in yeast 2014). Other studies of yeast and mammalian implicated Sec15 as the subunit that directly vesicle trafficking, however, suggest that the bound Rab GTPases on the surface of secretory exocyst holocomplex, including Sec3 and vesicles (Salminen and Novick 1989; Guo et al. Exo70, can be present on secretory vesicles 1999b), and Sec3 as the plasma-membrane- and that the polarized subcellular localization bound subunit and the spatial landmark for of Sec3 is dependent on an intact secretory exocyst-destined exocytosis (Finger et al. pathway and actin polymerization (Roumanie 1998). Subunit interactions of the exocyst com- et al. 2005; Bendezu and Martin 2011; Bendezu plex have been extensively studied using various et al. 2012). In addition, AP-1B, a vesicle-asso- methods in yeast and in mammals. These stud- ciated clathrin adaptor protein, which is re- ies revealed and confirmed stronger pairwise sponsible for basolateral protein sorting in ep- interactions, such as those between Sec3– ithelia, facilitated the recruitment of both Exo70 Sec5, Sec6–Sec8, and Sec10–Sec15 (Guo et al. and Sec8 to the secretory vesicle (Folsch et al. 1999a,b; Matern et al. 2001; Vegaand Hsu 2001; 2003). This finding supports the model in Munson and Novick 2006; Katoh et al. 2015; which all exocyst subunits—both Exo70- and Heider et al. 2016). Some exocyst interaction– Sec8-containing subcomplexes—are present based models proposed two four-subunit sub- on the vesicle. complex-architectures for both yeast and mam- To fulfill its tethering function following malian complexes. Here, the core module of vesicle delivery, the exocyst has to interact with Sec3, Sec5, Sec6, and Sec8 is connected to the the target membrane. This interaction is medi- vesicle-attached subcomplex of Sec10, Sec15, ated through direct binding of Sec3 and Exo70 Exo70, and Exo84 mainly through the Sec8– subunits with phosphatidylinositol(4,5)-bis- Sec10 interaction (Katoh et al. 2015; Heider phosphate (PtdIns(4,5)P2) located primarily et al. 2016). This supports previous cell frac- on the inner leaflet of the plasma membrane tionation studies showing distinct distribution (He et al. 2007; Liu et al. 2007; Zhang et al. of Sec10–Exo84 and Sec5–Sec6 cofractions in 2008; Shewan et al. 2011; Pleskot et al. 2015). rat pheochromocytoma cells (Moskalenko et al. The first studies of the exocyst in polarized ep- 2003). In mammals, several of the subunits are ithelial cells implicated the exocyst in mainly predicted to have different isoforms as a result basolateral vesicle trafficking to sites of cell– of alternative splicing (UniProt Consortium cell contacts (Grindstaff et al. 1998; Lipschutz 2015). Discussed later in this review, alternative et al. 2000). Yet, the finding that members of splicing of the exocyst genes might be a major the exocyst complex can directly bind with regulatory mechanism by which cells control PtdIns(4,5)P2, which can be located on the api- polarity and phenotype. cal surface of polarized mammalian epithelial cells (Di Paolo and De Camilli 2006; Gassama- Diagne et al. 2006; Martin-Belmonte et al. Exocyst in Trafficking and Plasma-Membrane 2007), suggested the potential that the exocyst Targeting may also take part in apical delivery under cer- Initial studies in budding yeast suggested that tain conditions. Although this exocyst–phos- six of the exocyst subunits traveled to the cell pholipid interaction may be crucial for exocytic membrane associated with exocytic vesicles events, the spatial and temporal control of exo- along actin cables, transported by the type V cyst-mediated exocytosis also hinges
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